HELENI. THAYER AND B. B. CORSON
2330
hydroxyadipaldehyde. The adipaldehyde derivative was also characterized as the tetraethyl mercaptal.
[CONTRIBUTION FROM
Vol. 70
These results show that. streptobiosamine is linked glycosidically a t position 4 of streptidine. RAHWAY, N. J.
RECEIVED FEBRUARY 14,1948
KOPPERS CO.,INC., MULTIPLEFELLOWSHIP ON TARSYNTHETICS, MELLON INSTITUTE]
Action of Sulfur on Certain Pyridine and Quinoline Derivatives. I. Action of Sulfur on 4-Picoline BY HELENI. THAYER AND E. E. CORSON The dehydropolymerizing action of sulfur on These results are similar to those of Aronstein and the picolines has not been previously noted, but von Nier0p.l who treated toluene with sulfur at certain examples of this action have been recorded 200' and 250-300' to obtain stilbene and tetrain the methylbenzene series. For example, i t is phenylthiophene, respectively. Likewise, Odd0 known that sulfur converts toluene to stilbene and and R&a2 obtained the sulfur-free compound 3,3'tetraphenylthiophene, and xylenes to dimethyl- biindole by treating indole with sulfur a t 115-125' stilbenes and dimethylbenzyls.' and sulfur-containing products a t higher reaction This paper describes the synthesis of several temperatures. higher molecular weight bases from 4-picoline by the action of sulfur. Five products were obtained: hydrogen sulfide, 1,2-di(4-pyridyl)-ethane (I), CHo CHa 1,2-di-(4-pyridyl)-ethylene (11), 1,2,3-tri-(4-pyridyl)- (-H~o) . propane (111) and 2,3,4,5tetra (4 pyridyl) - thiophene (IV). In the absence of sodium hydroxide Y Y the yield of tetrapyridylthiophene (IV) was negligible, but it was the main product (8540% yield) when the reaction mixCH=CH CHz-CHI ture contained a catalytic amount of sodium hydrox(IV) ide and the k a l reaction IA
0g
Q
+
- -
I
and tetrapyridylthiophene (IV) a t the expense of the saturated compounds of dipyridylethane (I) and tripyridylpropane (111). The product-distribution
CH-CH2
(VI
perature, length of reaction time, and sulfurpicoline ratio. At the lower temperatures, sulfur-free compounds (I, 11, and 111) resulted, whereas a t the higher temperatures the main product was the sulfur-containing tetrapyridylthiophene (IV)
.
(1) Aronstein and von Nierop, Rcc. :roo. chim.. 21, 448 (1902).
The structures of I and I1 were established as follows : (1) oxidation of these compounds to isonicotinic acid; ( 2 ) hydrogenation of I1 to I ; (3) dehydrogenation of I to 11; and (4) the synthesis of lJ2-di-(4-pyridyl)-ethylene(11) by the condensation of 4-pyridylaldehyde with 4-pico(2) Odd0 and Raffa, Gass. chim. it&, 69, 662 (1939).
THEACTIONOF SULFUR ON 4-PICOLINE
July, 1948
233 1
line. The structure of 1,2,3-tri-(4-pyridyl)-propane (111) was based on its oxidation to isonicotinic acid. Evidence for the structure of 2,3,4,5tetra-(4-pyridyl)-thiophene (IV) was threefold: (1) its synthesis from 1,2-di-(lpyridyl)-ethane (I); (2) its conversion to the sulfur-free compound (V) ; (3) the similarity of its spectrum in ui 3.60 the region 280-370 mp (Fig. 1) to that of 2,3,4,5tetraphenylthiophene. The synthesis of I V from 3.20 l,Z-di-(4-pyridyl)-ethane(I) was accomplished by heating the latter with sulfur as in the synthesis of tetraphenylthiophene from dibenzyl and sulfur,3 and tetrapyridylthiophene (IV) was degraded to 2.40 tetrapyridylbutane (V) with zinc and hydrochloric acid as in the reductive fission of tetra2.001 , I phenylthiophene to tetraphenylb~tane.~ The structure of 1,2,3,4-tetra-(4-pyridyl) -butane (V) 240 280 320 360 was based on its oxidation to isonicotinic acid, and Vmd. the conversion of V to I V by reaction with sulfur. Fig. 1.-Absorption curves of tetraphenylthiophene (A) Catalytic hydrogenation of 1,2-di-(4-pyridyl)- and tetra-(4-pyridyl)-thiophene (B) in 95% ethanol. ethane (1) in cyclohexane solution gave 1,2-di-(4piperidy1)-ethane (VI), whereas hydrogenation in 180'. Redistillation of the overhead showed it to be a t least 90% 4-picoline; no higher boiling material was ethanol gave the di-N-ethyl derivative (VII) .s present. The reaction product residue was stirred into
2.801
I
I
I
I
4
I
a mixture of ice and 50% sulfuric acid; unreacted sulfur was removed by filtration, and the filtrate was made alkaline with 30% sodium hydroxide solution. The oil layer was separated while warm. The water layer was extracted with benzene and the extract was added to the I i oil. The crude product, dark brown and semi-solid after removal of water and benzene, was distilled at about 3 mm. I into several fractions. These distillates crystallized in CH2-CHz the receiver and were purified by crystallization; the pot residue was a black, charred solid. Effect of Reaction Variables (Table I).-In the absence The various reaction mixtures were scrutinized of sodium hydroxide the main product was dipyridylfor intermediate products to serve as clues to the ethane; there was considerable tripyridylpropane, but reaction mechanism. In the benzene series, poly- little dipyridylethylene. Doubling the relative amount of (e. g., increasing the suIfur-picoline ratio from 1:2 meric thiobenzaldehyde, benzyl mercaptan and di- sulfur to 1 : l ) did not change the product-distribution, but it benzyl sulfide have been hypothesized as inter- increased the picoline conversion somewhat. The effect mediates in the reaction of toluene with sulfur be- of lengthening the reaction time was t o increase the cause they pyrolyze to certain of the end-products picoline conversion, partly due to the resulting higher reaction temperature. As remarked above, the of this reaction, rviz., stilbene and tetraphenylthio- final effect of sodium hydroxide was to favor the formation of phene.' However, in the present case, no analo- dipyridylethylene and tetrapyridylthiophene a t the gous intermediates were isolated to justify the expense of dipyridylethane and tripyridylpropane. 1,2-Di-(4-pyridyl)-ethme (I).-Repeated crystalliza; postulation of a reaction mechanism. tion of the fraction melting at 107-110' (b. p. 167-174 at 3 mm.) from cyclohexane-benzene (3:l) gave compact, Experimental colorless crystals, m. p. (capillary) 11O-11Io, f. p. (cool4-Picoline.-The 4-picoline (95+Y0 pure, b. p. 144.2- ing curve) 110.0-110.2O.6 144.4" (743 mm.), nmD1.5050, dzol 0.953) was a product of Anal. Calcd. for CIZH1PN2: C, 78.2; H, 6.6; N, 15.2; the Koppers Company, Inc. mol. wt., 184. Found: C, 77.8; H, 6.9; N, 15.0; mol. Reaction of 4-Picoline with Sulfur (below 200'7.wt., 189.' Yield data on several experiments are listed in Table I. The hydrochloride was precipitated from an alcohol The general procedure was to heat a mixture of 4-picoline solution of the base by hydrogen chloride; white crystalwith flowers of sulfur (with or without sodium hydroxide) line powder, 95% yield, m. p. 329-330' (dec.). in a 3-neck flask equipped with condenser, stirrer and Anal. Calcd. for C I ~ H ~ ~ N T ~C1, H C27.6. ~ : Found: thermometer. The mixture darkened and hydrogen sulfide was evolved. The final temperature of the re- C1, 27.5. 1,2-Di-(4-pyridyl)-ethylene (11).-Three fractions boilaction mixture depended upon the length of the heating period. After cooling, unreacted picoline was removed ing at 175-189' (2.6 mm.), 175-205' (2 mm.) and 193through a short column at about 45 mm. pressure, distilla- 220' (2 mm.), respectively, were combined and fractiontion being discontinued when the pot temperature reached ally crystallized from benzene to yield impure I and I:, the latter beingolong, white needles, m. p. 151-152 , (3) Szperl and Wieruse-Kowalski, Chem. Polski, 18, 19 (1917); f. p. 151.5-151.2
0 ci H
H
through Chem. Zenlr., 89, I, 909 (1918). (4) Fromm and Achert, Bcr., S6, 534 (1903). (5) This is another example of simultaneous N-a.lkyla.tionhydrogenation, see King, Baltrop and Walley, J . Chcm. Soc., 277 (1945); Adkins, Kuick. Farlow and Wojcik, THIS JOURNAL, 86, 2425 (1934).
.
(6) All melting points were corrected. The cooling curve temperatures listed were the initial and the final temperatures (when about 50% of the sample was frozen). (7) Molecular weights were determined by the method of Hanson and Bowman, I n d . Eng. Chcm., Anal. E d . , 11,440 (1939).
HELENI. THAYER AND B. B.
2332
VoI. 70
CORSON
TABLE I REACTION OF 4-PICOLINE WITH SULFUR (BELOW200') c
T,OC.
Hr.
Pic5
Reactants, moles S
. NaOH
Pic reacted,
yo
-
Products, wt. %
C I H ~ P ~CrHaPs
CnHsP8
TP4
Pot residue
Unaccounted for
9 143-166 4 4 0 71 52 2 21 0 9 16 12 137-174 3 3 0 77 46 6 22 0 15 11 12 140-155 3 1.5 0 53 60 4 14 0 10 12 24 140-171 3 1.5 0 71 48 4 24 0 8 16 7 135-160 4 8 0.075 65 32 15 4 0 17 32 4 8 0.075 94 9 0 0 72 I3 6 12 140-199 12 135-161 3 3 0.15 78 28 20 11 1 16 24 12 135-162 3 3 0.30 77 26 15 0 26 9 24 a Pic, CzH4P2, CzHzP2, CaHSPa, TP4 = 4-picoline, 1,2-di-(4-pyridyl)-ethane, l,%di-(4-pyridyl)-ethylene, 1,2,3-tri-(4pyridyl) -propane, 2,3,4,5-tetra-(4-pyridyl) -thiophene, respectively. TABLE I1 REACTION OF 4-PICOLINE WITH SULFUR c
T,"C. pic 2.5 150-300 0.05 2.8 175-330 .05 2.5 160-290 .05 2.5 160-290 -05 Based on picoline. Based on sulfur. Hr.
a
Reactants, moles NaOH
S
0.075 .0875
0.00025 .00025 ,00025 .00025
.loo
.125
Anal. Calcd. for CHHION?:C, 79.1; H, 5.5; N, 15.4; mol. wt., 182. Found: C, 78.8; H, 5.3; N, 15.6; mol. wt., 180. Its hydrochloride, precipitated from alcohol in 99% yield, was a white crystalline solid, m. p. 347" (sealed tube, dec.). Anal. Calcd. for C , Z H ~ O N Z . ~ HC1, C ~27.8. : Found: C1, 27.8. 1,2,3-Tri-(4-pyridyl)-prapane (111).-The fraction boiling at 230-242" (2 mm.) was repeatedly crystallized from ethyl acetate to yield'pale yellow crystals, m. p. Its melting point was de110-111', f. p. 109.9-109.3 pressed 10-12' by admixture with an equal amount f: di-(4-pyridyl)-ethane (I) which also melted at 110-111 Anal. Calcd. for CisHnNa: C, 78.5; H, 6.2; N, 15.3; mol. wt., 275. Found: C, 78.8; H, 6.3; N, 15.2; mol. wt., 282. Its hydrochloride, precipitated from alcohol in 85% yield, was a white hygroscopic powder, m. p. 230-232 (dec.). Anal. Calcd. C , ( I H ~ ~ N ~ . ~ HC1, C ~ :27.7. Found: C1, 27.4. Reaction of 4-Picoline with Sulfur (above 200').-At temperatures above 200' in the presence of catalytic amounts of sodium hydroxide, the main products were 2,3,4,5-tetra-(4-pyridyl)-thiophene (IV) and hydrogen sulfide. The data listed in Table I1 were obtained from small experiments in which hydrogen sulfide was swept out of the reaction mixture by nitrogen and collected in Ascarite preceded by pumice-sulfuric acid. Approximately the theoretical amount of hydrogen sulfide was recovered; the maximum utilization of sulfur was at the picoline-sulfur ratios of 4:6 and 4:7. The decreased yield of tetrapyridylthiophene obtained at the smallest pico1ine:sulfur ratio of 4: 10 (as compared with the theoretical ratio of 4:7) w m probably due to inclusion of product in the recovered excess sulfur. In typical larger scale reactions, a mixture of 4 moles of picoline, 8 moles of sulfur, and 0.025 mole of sodium hydroxide was heated for fourteen hours (final temperature ca. 245'). The reaction mixture was poured into acid and unreacted sulfur was removed by filtration; the acid filtrate was made alkaline and the precipitated tetrapyridylthiophene isolated ( 8 5 4 0 % yield).
.
.
(ABOVE
-
--
200")
HaS
Pic:S
% Yield
4:6 4:7 4:8 4: 10
101 98 97 100
Products-S,
P4T
€7
% Yield
0 0.02 0.5 1.5
89" 83b gob
78b
2,3,4,5-Tetra-(4-pyridyl)-thiophene (IV) .-The crude product gave about 80% yield of compound IV, m. p . 251.8-252.6", pale yellow crystals from methanol or pyridine. AnaE. Calcd. for C2rHlaNdS: C, 73.4; H, 4.1; N, 14.3; S, 8.2; mol. wt., 393. Found: .C,73.6; H, 4.0; N, 14.2; S, 8.4; mol. wt., 401. The hydrochloride, precipitated from ethanol in 95% yield, was a pale yellow hygroscopic solid, m. p. 283285" (dec.). Anal. Calcd. for C%Hl&N&4HCl: C1, 26.3. Found: C1, 26.0. Proof of Structure Oxidation of Compounds I, 11, 111 and V.-l,2-Di-(4pyridy1)-ethane (1.84 8.) in 100 cc. of water was oxidized at about 60" with 6 g. of potassium permanganate added in several portions during one and one-half hours. From the filtrate (at PH 3.6) two crops of isonicotinic acid were obtained, 1.81 g. (m. p. 317-319' (dec.)) and 0.36 g . (m. p. 314-316' (dec.)). The neutral equivalents were 124.3 and 125.6, respectively, compared with the theoretical of 123.1. The yield of isonicotinic acid was therefore 87%. In similar manner, 1,2-di-(4-pyridyl)ethylene, 1,2,3-tri-(4-pyridyl) -propane, and 1,2,3,4tetra-(4-pyridyl) -butane were oxidized to isonicotinic acid in 76, 84 and 74% yields, respectively. Synthesis of 1,2-Di-(4-pyridyl)-ethyleae (11) from 4Pyridylaldehyde and 4-Picoline.-Selenium dioxide oxidation of 4-picoline in wet dioxane at 90' under nitrogen produced a small yield of .l-pyridylaldehyde, b. p. 6874" (11 mm.), n% 1.5382, m. p. of phenylhydrazone 177.5-178.5O.8 4-Pyridylaldehyde (1.79 8.) was heated with 1.56 g. of 4-picoline and 2.28 g. of zinc chloride for sixteen hours at 200-215'. The reaction mixture was cooled, dissolved in 20 cc. of 3 N sulfuric acid and two 5-g. portions of sodium hydroxide pellets were added. The cooled alkaline solution was repeatedly extracted with ether followed by chloroform. Removal of the solvent left a semi-solid product which was filtered; the filtrate was distilled (b. p. 182-189' (4 mm.)) to yield a distillate which partially solidified. The weight of the combined solids was 0.41 g . (13% yield). Three crystallizations from benzene with boneblacking gave colorless needles ( 8 ) Wibaut. Kooyman and Boer, Rcc. f m v . chim., 64, 30 (1945)
July, 1948
THEACTION OF SULFUR ON 4-PICOLINE
which melted at 151-152' and showed no depression in melting point when admixed with di-(4-pyridyl)-ethylene (11). Anal. Calcd. for ClzHloNz: C, 79.1; H, 5.5; N, 15.4. Found: C.78.9; H, 5.3; N. 15.7. Hydrogenation of 1,2-Di-(4-pyridyl) -ethylene (11) to 1,2-Di-(4-pyridyl) -ethane (I) .-Hydrogenation of dipyridylethylene in methanol with platinum gave a 76% yield of product which melted at 111-112' and did not depressthemelting point of lJ2-di-(4-pyridyl)-ethane(I). Anal. Calcd. for ClzHl~N2: C, 78.2; H, 6.6; N, 15.2. Found: C, 78.2; H, 6.7; N, 15.3. Dehydrogenation of l,Z-Di-(4-pyridyl)-ethane (I) to 1,2-Di-(4-pyridyl)-ethylene (11).-Dipyridylethane (117 9.) was passed o:er 60 g. of a ferruginous dehydrogenation catalyst9 a t 600 , atmospheric pressure, and one second contact time, with 15 volumes of diluent steam. The catalyst carbonized to the extent of 10.9 weight per cent. The catalyzate was a mixture of solid, oil and water (ammoniacal odor), from which were separated 30 g. of unchanged dipyridylethane, 20 g. of dipyridylethylene, and 14 g. of 4-picoline (identified as methiodide, m. p. and mixed m. p. 152-153.5'). Sulfuration of l,Z-Di-(4-pyridyl)-ethane to 2,3,4,5Tetra-(4-pyridyl)-thiophene.-A mixture of 3.68 g. of lJ2-di-(4-pyridyl)-ethane(I) and 1.60 g. of sulfur was heated for eight and one-half hours at 170-240'; 0.85 g. of hydrogen sulfide was evolved, 0.75 g. of sulfur was recovered, and 2.5 g. of a reddish-brown solid was obtained. Crystallization from methanol gave 1.69 g. of solid melting at 246-250', and recrystallization gave yellow crystals melting a t 251.5-252.5' whose melting point was not depressed by admixture with 2,3,4,5-teti-a(4-pyridyl) -thiophene (IV). Anal. Calcd. for C ~ ~ H I O N ~C,S :73.4; H, 4.1; N, 14.3. Found: C, 73.6; H, 4.2; N, 14.2. Reductive Desulfurization of 2,3,4,5-Tetra-(4-pyridyl) thiophene (JY) to 1,2,3,4-Tetra-(4-pyridyl)-butane (V) .A mixture of 7.84 g. of tetrapyridylthiophene, 20 g. of zinc dust, and 100 cc. of 25% hydrochloric acid was refluxed for two hours; 25 cc. of 25% hydrochloric acid was added and the refluxing was continued for another hour. The grayish solid was filtered, boiled for a short time with 25% caustic to decompose the zinc chloride complex, and the mixture was filtered. The solid was extracted with dilute hydrochloric acid, and the nitrogen base (4.21 g., 57% yield) was precipitated from the extract by caustic (m. p. 262-265' after recrystallization from 96% ethanol). Anal. Calcd. for CarHfzNd: C, 78.6; H, 6.1; N, 15.3; mol. wt., 366. Found: C, 78.5; H, 6.1; N, 15.4; mol. wt. (Rast), 347. Sulfuration of lJ2,3,4-Tetra-(4-pyridyl)-butane(V) to 2,3,4,5-Tetra-(4-pyridyl)-thiophene (IV) .-A mixture of 1.44 g. of tetrapyridylbutane and 0.75 g. of sulfur was heated for two and one-half hours a t 140-245' in a slow stream of nitrogen; 0.38 g. of hydrogen sulfide was collected in Ascarite and 0.31 g. of sulfur was recovered. The filtrate was made alkaline and 1.36 g. (89% yield) of tan-colored precipitate was filtered. Recrystallization from methanol gave pale-yellow crystals (m. p . 251.5252.5'). whose melting point was not depressed by admixture with 2,3,4,5-tetra-(4-pyridyl) -thiophene (IV). Anal. Calcd. for Cz,HlsN63: C, 73.4; H, 4.1; N, 14.3;. S,-8.2. Found: C, 73.7; H, 4.3; N, 14.6; S,
-
2333
g. of material boiling at 125-130' (2 mm.) which solidified
in the receiver. Crystallization from Skellysolve Bbenzene (6:1) gave 68 g. of colorless crystals (m. p. 110-113.5') which rapidly formed a carbonate on exposure to air. A recrystallized sample of carbonate-free material melted at 113-114". Anal. Calcd. for C12H2&: C, 73.4; H, 12.3; N, 14.3. Found: C,73.4; H, 12.1; N, 14.3. The hydrochloride (colorless powder, 96% yield) melted at 366-368" (dec.). Anal. Calcd. for C12H~Nz.2HCl: C1, 26.3. Found: C1, 26.0. Hydrogenation of l,Z-Di-(4-pyridyl)-ethane (I) to Di(N-ethy1-4-piperidyl) -ethane (VII) .-Dipyridylethane (18 9.) was hydrogenated in ethanol at 90 atrn. and 200220' with nickel. The crude product (21 g.) boiled a t 139-143 ' (1.5 mm.) ; redistilled product (n"D 1.4836, dm4 0.9005) boiled a t 153-156' (3.5 mm.). The colorless liquid base formed a solid hydrate which dehydrated over phosphorus pentoxide. The hydrochloride was obtained in 91% yield, a white, hygroscopic powder. Anal. Calcd. for Cl8H3zN2.2HC1: C1, 21.8. Found: C1, 21.8. The piczate, yellow needles from benzene, melted a t 178.5-180 Anal. Calcd. for CldIaiNz.2CsHoNaOr: C, 47.3; H, 5.4. Found: C, 47.7; H, 5.4. Ethylation of 1,2-Di-(4-piperidyl) -ethane (VI) .-An ethanol solution (25 cc.) of 5.9 g. of dipiperidylethane and 9.8 g. of ethyl iodide was refluxed for two and one-half hours. The solid (9.8 g.), which separated on standing overnight, was filtered and treated with 65 cc. of 4% potassium hydroxide. The mixture was ether extracted, and the solid recovered from the ether was shaken with benzenesulfonyl chloride in 10% caustic. The solid sulfonamide of the non-ethylated dipiperidylethane was filtered and the filtrate was ether extracted. Double distillation of the ether-soluble oil gave a heart-cut (b. p. 149-150' (2.5 mm.) n% 1.4839) which formed a picrate (m. p. 178.5-180') which showed no depression with the picrate of compound VII. Anal. Calcd. for Ci&ZNz*2CeHaNaOr: C, 47.3; H, 5.4. Found: C, 47.0; H, 5.3.
.
Acknowledgment.-Thanks are expressed to J. E. Nickels, B. F. Tatterson, and J. J. McGovern for assistance in dehydrogenation, hydrogenation and spectroscopy, respectively, and to J. L. Keller for initiation of the early phases of the work. Summary 1,2-Di-(4-p yridyl) -ethane, 1,2-di-(4-pyridy l)ethylene, 1,2,3-tri-(4-pyridyl)-propane and 2,3,4,5-tetra-(4-pyridyl)-thiophenewere obtained from the reaction of 4-picoline with sulfur, the productdistribution depending upon the conditions. 2,3,4,5-Tetra-(4-pyridyl)-thiophenewas converted to 1,2,3,4-tetra-(4-pyridyl)-butane by reductive desulfurization. 1,2-Di-(4-pyridyl)-ethaneand 1,2,3,4-tetra-(4pyridy1)-butane reacted with sulfur to form 2,3,7.8. 4,5-tetra- (4-pyridyl)-thiophene. Hydrogenation of 1,2-Di-(4-pyridyl)-ethane (I) to 1,21,2-Di-(4-pyridyl)-ethanewas hydrogenated in Di-(4-piperidyl)-ethane (VI) .-Dipyridylethane (114 9.) cyclohexane solution to 1,2-di-(4-piperidyl)-ethwas hydrogenated in 300 cc. of cyclohexane at 135 atm. and 175-190' with nickel.10 Distillation yielded 86 ane, and in ethanol solution to 1,2-di-(N-ethyl-4piperidyl)-ethane. (9) Kearby, U. S: Patent 2,395,876 (1946). (10) Ipatieff and Corson, I n d . Eng. Chem., SO, 1039 (1938).
PITTSBURGH, PA.
RECEIVED FEBRUARY 13, 1948
